Nitric Oxide-Releasing Drug Glyceryl Trinitrate Targets JAK2/STAT3 Signaling, Migration and Invasion of Triple-Negative Breast Cancer Cells.

Sarra Bouaouiche,Olivier Burgy,Cindy Racoeur,Stéphanie Plenchette,Silvia Ghione,Valentin Derangère,Ali Bettaieb,Randa Sghaier

doi:10.3390/ijms22168449

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive disease with invasive and metastasizing properties associated with a poor prognosis. The STAT3 signaling pathway has shown a pivotal role in cancer cell migration, invasion, metastasis and drug resistance of TNBC cells. IL-6 is a main upstream activator of the JAK2/STAT3 pathway. In the present study we examined the impact of the NO-donor glyceryl trinitrate (GTN) on the activation of the JAK2/STAT3 signaling pathway and subsequent migration, invasion and metastasis ability of TNBC cells through in vitro and in vivo experiments. We used a subtoxic dose of carboplatin and/or recombinant IL-6 to activate the JAK2/STAT3 signaling pathway and its functional outcomes. We found an inhibitory effect of GTN on the activation of the JAK2/STAT3 signaling, migration and invasion of TNBC cells. We discovered that GTN inhibits the activation of JAK2, the upstream activator of STAT3, and mediates the S-nitrosylation of JAK2. Finally, the effect of GTN (Nitronal) on lung metastasis was investigated to assess its antitumor activity in vivo.

Highlights

Triple-negative breast cancer (TNBC) is a highly aggressive disease with invasive and metastasizing properties associated with a poor prognosis
We examined the ability of glyceryl trinitrate (GTN), a nitric oxide (NO)-releasing drug, to counteract the IL-6/JAK2/signal transducer and activator of transcription-3 (STAT3) axis migration, invasion and metastasis of TNBC cells
We found that carboplatin induces an increase in IL-6 at the mRNA level in TNBC cells

Summary

Introduction

Triple-negative breast cancer (TNBC) is a highly aggressive disease with invasive and metastasizing properties associated with a poor prognosis. The STAT3 signaling pathway has shown a pivotal role in cancer cell migration, invasion, metastasis and drug resistance of TNBC cells. In the present study we examined the impact of the NO-donor glyceryl trinitrate (GTN) on the activation of the JAK2/STAT3 signaling pathway and subsequent migration, invasion and metastasis ability of TNBC cells through in vitro and in vivo experiments. We found an inhibitory effect of GTN on the activation of the JAK2/STAT3 signaling, migration and invasion of TNBC cells. TNBC patients present higher chemosensitivity than for other subtypes of breast cancer, their prognosis remains worse [2]. STAT3 signaling pathways, activated through many cytokines (such as Interleukin-6 (IL-6), IL-10) and growth published maps and institutional affiliations

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Results

Conclusion